Am J Cancer Res 2013;3(5):446-464
Original Article
Clinical implications for loss or diminution of expression of Raf-1 kinase
inhibitory protein and its phosphorylated form in ductal breast cancer
Fahd Al-Mulla, Milad S Bitar, Jean Paul Thiery, Tan Tuan Zea, Devasis Chatterjee, Lindsay Bennett, Sungdae Park, Joanne
Edwards, Kam C Yeung
Department of Pathology, Molecular Pathology Unit, Faculty of Medicine, Kuwait University, Health Sciences Centre, Safat, Kuwait;
Department of Pharmacology, Faculty of Medicine, Kuwait University, Health Sciences Centre, Safat, Kuwait; Department of
Biochemistry, National University of Singapore, #02-03, MD7, 8 Medical Drive, Singapore, 117597; Department of Medicine,
Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI, USA; Institute of Cancer, MVLS,
McGregor Building, University of Glasgow, Glasgow, U.K. G128QQ; Department of Biochemistry and Cancer Biology, College of
Medicine, Health Science Campus, University of Toledo, Toledo, Ohio, USA
Received September 7, 2013; Accepted October 11, 2013; Epub November 1, 2013; Published November 15, 2013
Abstract: Raf Kinase inhibitory protein (RKIP) is a well-established metastasis suppressor that is frequently downregulated in
aggressive cancers. The impact of RKIP and its phosphorylated form on disease-free survival (DFS) and other
clinicopathological parameters in breast cancer is yet to be discovered. To this end, we examined RKIP expression in 3
independent breast cancer cohorts. At the Protein level, loss or reduced total RKIP expression was associated with large-sized
tumors characterized by high proliferative index, high-grade and diminished estrogen (ER) and progesterone receptor
expression. Loss or diminution of RKIP expression was significantly associated with shorter DFS in all cohorts. Moreover, the
complete loss of p-RKIP was an independent prognostic factor using multivariate analysis in operable invasive ductal breast
cancer. We show for the first time that ER, partly, drives RKIP expression through MTA3-Snail axis. Consistent with this finding,
we found that, at the mRNA level, RKIP expression varied significantly across the different molecular subtypes of breast cancer
with the Luminal (ER+) subtype expressing high levels of RKIP and the more aggressive Claudin-low (ER-) subtype, which
depicted the highest epithelial to mesenchymal transition (EMT) registered the lowest RKIP expression levels. In conclusion,
loss of expression/diminution of RKIP or its phosphorylated form is associated with poor diseases-free survival in breast cancer.
Determining the expression of RKIP and p-RKIP adds significant prognostic value to the management and subtyping of this
disease. (ajcr0000227).
Keywords: RKIP, PEBP1, ERK, estrogen receptor, aggressive cancer, breast cancer, Luminal, claudin-low, ERBB2, basal,
prognosis, disease-free survival
Address correspondence to: Dr. Fahd Al-Mulla, Department of Pathology, Molecular Pathology Unit, Faculty of Medicine, Health
Sciences Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Tel: 965-24986233; Fax: 965-25338905; E-mail:
fahd@al-mulla.org
Original Article
Clinical implications for loss or diminution of expression of Raf-1 kinase
inhibitory protein and its phosphorylated form in ductal breast cancer
Fahd Al-Mulla, Milad S Bitar, Jean Paul Thiery, Tan Tuan Zea, Devasis Chatterjee, Lindsay Bennett, Sungdae Park, Joanne
Edwards, Kam C Yeung
Department of Pathology, Molecular Pathology Unit, Faculty of Medicine, Kuwait University, Health Sciences Centre, Safat, Kuwait;
Department of Pharmacology, Faculty of Medicine, Kuwait University, Health Sciences Centre, Safat, Kuwait; Department of
Biochemistry, National University of Singapore, #02-03, MD7, 8 Medical Drive, Singapore, 117597; Department of Medicine,
Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI, USA; Institute of Cancer, MVLS,
McGregor Building, University of Glasgow, Glasgow, U.K. G128QQ; Department of Biochemistry and Cancer Biology, College of
Medicine, Health Science Campus, University of Toledo, Toledo, Ohio, USA
Received September 7, 2013; Accepted October 11, 2013; Epub November 1, 2013; Published November 15, 2013
Abstract: Raf Kinase inhibitory protein (RKIP) is a well-established metastasis suppressor that is frequently downregulated in
aggressive cancers. The impact of RKIP and its phosphorylated form on disease-free survival (DFS) and other
clinicopathological parameters in breast cancer is yet to be discovered. To this end, we examined RKIP expression in 3
independent breast cancer cohorts. At the Protein level, loss or reduced total RKIP expression was associated with large-sized
tumors characterized by high proliferative index, high-grade and diminished estrogen (ER) and progesterone receptor
expression. Loss or diminution of RKIP expression was significantly associated with shorter DFS in all cohorts. Moreover, the
complete loss of p-RKIP was an independent prognostic factor using multivariate analysis in operable invasive ductal breast
cancer. We show for the first time that ER, partly, drives RKIP expression through MTA3-Snail axis. Consistent with this finding,
we found that, at the mRNA level, RKIP expression varied significantly across the different molecular subtypes of breast cancer
with the Luminal (ER+) subtype expressing high levels of RKIP and the more aggressive Claudin-low (ER-) subtype, which
depicted the highest epithelial to mesenchymal transition (EMT) registered the lowest RKIP expression levels. In conclusion,
loss of expression/diminution of RKIP or its phosphorylated form is associated with poor diseases-free survival in breast cancer.
Determining the expression of RKIP and p-RKIP adds significant prognostic value to the management and subtyping of this
disease. (ajcr0000227).
Keywords: RKIP, PEBP1, ERK, estrogen receptor, aggressive cancer, breast cancer, Luminal, claudin-low, ERBB2, basal,
prognosis, disease-free survival
Address correspondence to: Dr. Fahd Al-Mulla, Department of Pathology, Molecular Pathology Unit, Faculty of Medicine, Health
Sciences Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Tel: 965-24986233; Fax: 965-25338905; E-mail:
fahd@al-mulla.org
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American Journal of Cancer Research
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